11-112226446-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000317.3(PTS):​c.3G>T​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

PTS
NM_000317.3 start_lost

Scores

5
4
7

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.95
Variant links:
Genes affected
PTS (HGNC:9689): (6-pyruvoyltetrahydropterin synthase) The enzyme encoded by this gene catalyzes the elimination of inorganic triphosphate from dihydroneopterin triphosphate, which is the second and irreversible step in the biosynthesis of tetrahydrobiopterin from GTP. Tetrahydrobiopterin, also known as BH(4), is an essential cofactor and regulator of various enzyme activities, including enzymes involved in serotonin biosynthesis and NO synthase activity. Mutations in this gene result in hyperphenylalaninemia. [provided by RefSeq, Oct 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 7 pathogenic variants. Next in-frame start position is after 204 CDS bases. Genomic position: 112230643. Lost 0.466 part of the original CDS.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-112226446-G-T is Pathogenic according to our data. Variant chr11-112226446-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2704000.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTSNM_000317.3 linkc.3G>T p.Met1? start_lost Exon 1 of 6 ENST00000280362.8 NP_000308.1 Q03393

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PTSENST00000280362.8 linkc.3G>T p.Met1? start_lost Exon 1 of 6 1 NM_000317.3 ENSP00000280362.3 Q03393

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1427080
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
706356
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

6-Pyruvoyl-tetrahydrobiopterin synthase deficiency Pathogenic:1
Dec 18, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects the initiator methionine of the PTS mRNA. The next in-frame methionine is located at codon 69. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with tetrahydrobiopterin-deficient hyperphenylalaninemia (PMID: 22237589, 29499199, 30926181). This variant disrupts a region of the PTS protein in which other variant(s) (p.Thr67Met) have been determined to be pathogenic (PMID: 11438997, 11694255, 16850690, 22237589). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.47
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.36
T;.
Eigen
Benign
-0.030
Eigen_PC
Benign
0.073
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.90
D;D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Uncertain
0.29
D
PROVEAN
Benign
-0.65
N;N
REVEL
Uncertain
0.57
Sift
Benign
0.052
T;D
Sift4G
Benign
0.21
T;D
Polyphen
0.085
B;.
Vest4
0.91
MutPred
0.95
Gain of glycosylation at S2 (P = 0.0649);Gain of glycosylation at S2 (P = 0.0649);
MVP
1.0
ClinPred
0.99
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.6
Varity_R
0.75
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-112097169; API